tbuckley/cabot-search huggingface dataset:
HULL’S MAGIC BOX: BUILDING THE CASE FOR CLINICAL TRIALS USING ARGININE METHYLATION INHIBITORS AGAINST GBM
Authors: Antonia Barry, Sabrina Samuel, Amr Moursi, Srihari Deepak, Chittoor Rajaraman, Shailendra Achawal, Ricky Akinkuolie, Lauric Feugere, Alexander Iles, Vicky Green, Lucy Stead, Mark Wade, John Greenman, Pedro Beltran-Alvarez
Journal: Neuro-Oncology (2023)

Abstract AIMS • Assess/evaluate transcriptomic changes in GBM, maintained on a microfluidics system, in response to treatment with arginine methylation inhibitor GSK3368715, currently in clinical trials, to identify novel therapeutic strategies, synergising with personalised patient care and precision medicine • Investigate molecular differences between healthy brain and GBM maintained on-chip in response to GSK3368715, including proliferation, apoptosis and splicing. METHOD GBM biopsies from Hull Royal Infirmary, or healthy mouse brain tissues, were maintained on-chip for 8- days and perfused with GSK3368715-treated media, at 3 μl/min, mimicking the in vivo environment. RNA- sequencing determined thousands of differentially expressed genes and alternative splicing (AS) events resulting from GSK3368715 treatment. Immunohistochemistry displayed the effect of GSK3368715 on healthy mouse brain tissue to ascertain the specificity of the arginine methylation inhibitor in leading to GBM apoptosis. RESULTS RNA-sequencing showed highly significant GO-term-enrichment in ribosome and translation pathways, suggesting decreased protein synthesis capacity after GSK3368715 treatment. Additionally, several hundreds of genes were found to be undergoing AS, compatible with a mechanism where changes in the arginine methylation pattern of spliceosome member FUS, upon GSK3368715 treatment, contribute to AS. Of these events, 136 (more than expected by chance, χ2 = 7.16, p = 0.007) were known FUS splicing targets. GO-term-enrichment of these AS events was found in DNA damage and cell death . Together these results are consistent with immunohistological findings that GSK3368715 causes apoptosis in GBM-on-chip tissue, in a specific manner. CONCLUSIONS Our results highlight an exciting potential therapeutic target for GBM, via induction of alternative splicing path- ways, through arginine methylation inhibition with GSK3368715.
DEfiNING SPATIAL HETEROGENEITY OF A NOVEL LIVING BIOBANK OF POST-SURGICAL RESIDUAL GLIOBLASTOMA TO DEVELOP STRATEGIES FOR TARGETED THERAPY
Authors: Connor McGarrity-Cottrell, Katie Myers, Mark Dunning, Veejay Bagga, Saurabh Sinna, Yahia Al-Tamimi, Ola Rominiyi, Spencer Collis
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma is the most common cancer arising within the brain accounting for &amp;gt;2,000 deaths/year in the UK. Current standard-of-care therapy consists of maximal safe surgical resection followed by radiochemotherapy which activates the cellular DNA damage response (DDR). However, disease prognosis remains poor (median OS ~12-15 months). This stagnation in the development and clinical translation of novel therapeutics is largely attributed to extensive inter- and intra-tumoral heterogeneity and resistant glioma stem cell (GSC) niches. Traditionally, primary ex vivo and in vivo models of glioblastoma have been generated from the resected tumour mass potentially omitting the post-surgical residual tumour cells that give rise to disease recurrence and morbidity. METHOD Multiple parallel primary ex vivo GSC cell models were generated from anatomically discrete regions of en-bloc partial lobectomy glioblastoma specimens to produce 3D models of resected (tumour “core”) and typically residual (distal invasive tumour “edge”) GSC niches. These models were characterised using an array of biomolecular techniques and 3D based assays. RESULTS Preliminary RNA-seq analyses revealed largely divergent transcriptional landscapes for resected vs residual GSCs and protein expression/immunofluorescence analyses also identified key differences in GSC and DDR ex- pression, and subsequent cellular responses to current standard-of-care radio-chemotherapy regimens. CONCLUSIONS These data reveal phenotypic relationships between GSC “stemness” and DDR activity, therefore highlighting the potential clinical relevance of our novel parallel resected and residual ex vivo glioblastoma models. Characterisation of further models from within our 3D GSC biobank will also aid evaluation of novel therapeutics capable of targeting post-surgical GSC subpopulations leading to improved disease outcomes.
RECOVER REALITY FEASIBILITY TRIAL: INVESTIGATING THE FEASIBILITY OF IMMERSIVE TECHNOLOGIES TO ENHANCE NEUROREHABILITATION EDUCATION AFTER NEUROSURGERY FOR BRAIN CANCER
Authors: William Bolton, Rohit Sinha, Oluwaseyi Adebola, Elisa Stephenson, Sara Cooper, Seonaid Ewan, Ryan Mathew
Journal: Neuro-Oncology (2023)

Abstract AIMS Neurorehabilitation is fundamental to better outcomes for those recovering from neurosurgery for brain cancer. Access to this essential therapy is limited by resource shortages and unfulfilled therapy needs lead to longer hospital stays. Immersive technologies such as virtual reality (VR) could be used to augment neurorehabilitation in a self-directed, safe, virtual environment. The aim of this study is to demonstrate the feasibility of a VR rehabilitation programme in an acute neurosurgical inpatient environment to augment neurorehabilitation. METHOD A single group, feasibility study was conducted in a tertiary UK neurosurgical department. Patients aged 16 and over who had undergone a neurosurgical intervention for brain tumours were eligible. Participants were offered a VR session at least once per day for the first 14 days post-surgery/injury or until discharge, whichever comes first, with reasons for non-engagement collected. Primary outcomes were feasibility outcomes, and secondary outcomes included rehabilitation engagement and length of stay. RESULTS Data collection is ongoing. At submission we have n=6 participants who used the VR. A seventh participant who was screened for inclusion declined, citing anxiety over causing headaches as the reason. All six participants used the VR on either post operative day 2 or day 3. Although offered VR on the immediate day after surgery, participants declined due to nausea or pain. CONCLUSIONS If this present study demonstrates feasibility of using VR in patients after neurosurgery for brain cancer, a randomised clinical effectiveness study with health-economics analysis will follow to inform widespread adoption into practice.
LONG-TERM POST-MARKETING SURVEILLANCE DATA FROM ELDERLY PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANCIES TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Maciej M Mrugala, Wenyin Shi, Fabio M Iwamoto, Martina Heidemann, Rimas V Lukas, Joshua D Palmer, John H Suh, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma (GBM) has a poor prognosis, which is compounded by an increase in treatment-related toxicity with age. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. Subgroup analysis of the phase 3 EF-14 study demonstrated TTFields therapy to be well-tolerated in patients ≥65 years with newly diagnosed (nd) GBM. We report safety data in elderly patients from a global post- marketing surveillance (PMS) analysis of patients with central nervous system (CNS) malignancies receiving TTFields. METHOD PMS data was collected from patients receiving TTFields (October 2011–March 2022) in North America, Europe, Middle East, Africa, and Japan. Adverse events (AEs) were categorized using MedDRA version 25.1. RESULTS Overall, 25,898 patients were included (diagnoses: ndGBM [68%], recurrent GBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other [2%]). Of these, 7808 patients (30%) were elderly (&amp;gt;65 years). 75% of elderly patients experienced ≥1 AE, with 57% related to TTFields; comparable frequencies to the overall population (73% and 56%, respectively). The most common treatment-related AE in elderly patients was skin reaction (45%; overall population: 43%). Incidence of treatment-related fall and fracture in elderly patients was 1% and &amp;lt;1%, respectively. Incidence of treatment-related ‘quality-of-life decreased’ was 2% (elderly and overall). No systemic toxicities were reported, regardless of age group. CONCLUSIONS These real-world data demonstrate TTFields has a tolerable safety profile in elderly patients with CNS malignancies, consistent with elderly subgroup data from EF-14, and with no new safety signals. Most AEs were localised, manageable, mild–moderate skin reactions.
INVESTIGATING LOCAL RECURRENCE IN SECONDARY BRAIN TUMOURS
Authors: Joshua Suppree, Michael D Jenkinson, Rasheed Zakaria
Journal: Neuro-Oncology (2023)

Abstract AIMS Brain metastases result in considerable morbidity and mortality. Modern treatment strategies are increasingly omitting radiation therapy after surgical resection of these tumours. We investigated the rate of local recurrence in patients who had undergone surgery for brain metastasis in a single-institution study and compared it to the literature through a comprehensive meta-analysis. METHOD Patients undergoing surgery for a brain metastasis were identified and their records reviewed. Data on treatment and outcome was extracted and analysed. A systematic-review and meta-analysis, registered in PROSPERO (CRD42023391637), was conducted following the PRISMA statement. RESULTS The single-institution study comprised 358 cases, 40% (n=142) male and 60% (n=216) being female with a median age at surgery of 60 years (range 23-85 years). The most frequent primary cancer was lung cancer affecting 35% (n=126), followed by breast cancer (24%, n=87) and malignant melanoma (13%, n=47). Among the cases 142 underwent surgery without any adjuvant radiation. The median freedom from local recurrence at 12-months for this population was 38.3% (95% CI 13.4, 44.6). The meta-analysis encompassed three studies, with a total of 170 cases. Freedom from local recurrence at 12-months was found to be 42.4% (95% CI 34.9 - 50.1) following surgery alone. CONCLUSIONS We define for the first time the rates of local recurrence following surgery alone for brain metastases with a large single-centre series and a meta-analysis. As radiation is increasingly being omitted in these cases, caution should be exercised, and more investigation of the factors associated with local recurrence after surgery and how they be modified are required.
DUAL PET IMAGING OF NEOPLASTIC AND INflAMMATORY BIOMARKERS IN HIGH GRADE GLIOMA
Authors: Bandar Alfaifi, Alan Jackson, Rainer Hinz, Daniel Lewis, David Coope
Journal: Neuro-Oncology (2023)

Abstract AIMS To characterize spatial distributions of 18kDa translocator protein (TSPO) and amino acid uptake as measured through dynamic [11C] (R)-PK11195 and [11C]-methionine PET in high-grade glioma. METHOD Twelve patients with newly diagnosed high-grade glioma underwent dual PET studies. [11C] (R)-PK11195 binding potential (BPND) maps were generated using simplified reference tissue model with grey-matter cerebellar time- activity-curve as tissue input-function. [11C]-methionine uptake was calculated as tumour-to-background ratio (TBR). Volumes of interest (VOIs) were defined on T1W post-contrast MRI as contrast-enhancing (CE) tumour and a ‘peritumoural’ region 5mm from the CE edge. Voxel-wise comparison of the tracers used Pearson’s correlation coeffcient. VOIs were furthermore subdivided into higher/lower TSPO (BPND &amp;gt; 0.17) and higher/lower methionine (TBR &amp;gt; 1.7). RESULTS Within the CE, voxel-wise comparison showed a strong correlation (r &amp;gt; 0.7) in eight subjects, moderate correlation (r &amp;gt; 0.5) in three subjects and weak correlation (r &amp;lt; 0.5) in one subject. Volume (mm3) with high BPND/high TBR accounted for 62±29% whereas high BPND/low TBR accounted for 13±16%. Within the peritumoral area, there was a small reduction in the proportion of subjects in the strong correlation group (6/12) but the pro- portion of voxels with higher TSPO binding and lower methionine uptake was substantially greater (35±16%). CONCLUSIONS Within high-grade glioma, there is a strong overall correlation between TSPO expression and amino acid uptake. However, in the peritumoural region there are areas of elevated TSPO expression without increased methionine uptake which could represent an inflammatory component or a discrete neoplastic cell population that may not be adequately defined with standard imaging biomarkers.
DEVELOPING 3D PRINTING MODELS OF BRAIN TUMOURS
Authors: Rafael Ballesteros-Cillero, Jessica Valli, Ferry P W Melchels, Nicholas R Leslie
Journal: Neuro-Oncology (2023)

Abstract AIMS To succeed in clinical trials for glioblastoma we need in vitro models capable of more faithfully replicating dis- ease biology and more accurately predicting patient drug responses. To this end, new bioprinting technologies have the potential to biofabricate clinically relevant biomimetic tissues which can accelerate drug discovery and additionally serve as a platform for personalized medicine. METHOD We evaluated the effect of individual biomaterials and combinations of biomaterials, including decellularised pig brain extracellular matrix (dECM), fibrin, gelatin-methacryloyl (GelMA), hyaluronic acid-methacrylate (HAMA), Matrigel and alginate, on the proliferation and invasion of aggressive brain cancer cells (U87) in vitro. Cell viability was assessed using propidium iodide. Invasiveness was studied employing confocal microscopy. Data generated from Z-stacks was analysed using ImageJ to determine the size and circularity of cells. RESULTS Although Matrigel supports rapid cell proliferation and invasion, it has mechanical properties unsuited to bio- printing. In contrast, HAMA displays a pronounced shear-thinning behaviour and rapid controllable photo- crosslinking. Combinations of HAMA-fibrin provided results comparable to those seen with Matrigel or HAMA- Matrigel. However, high levels of crosslinking affected these biomaterial mixtures, resulting in a decreased ability of cells to grow and spread. CONCLUSIONS Initial results indicate that the addition of fibrin to HAMA promoted the growth and spreading of U87 cells. In further work, we aim to improve our printed constructs by including porcine brain dECM, microglia and recently established cell lines from paediatric patients. The project will test whether these bioprinted models can provide drug testing data with closer results to human disease than current, simpler alternatives.
END OF LIFE CARE IN BRAIN TUMOUR PATIENTS: DEMOGRAPHICS AND PREFERENCES
Authors: Radvile Mauricaite, Kerlann Le Calvez, Joanne Droney, Matthew Williams
Journal: Neuro-Oncology (2023)

Abstract AIMS We used a regional NHS Electronic Palliative Care Coordination System (Coordinate My Care) to understand patient preferences and priorities for care at end-of-life. We present data on patient demographics and preferences and factors influencing the location of death in a primary brain tumour patient cohort. METHOD We identified all primary brain tumour patients from NW and SW London on the system. We examined patient demographics and compared the recorded preferred place of death (PPD) with the actual place and explored how patient demographics differ according to this. RESULTS Our dataset contains 1437 patients. 55% were male and 53% were 65 or older. 1222 (85%) were deceased. Of patients that had a recorded preference (N=987), 30 (3.0%) had hospital recorded as one of their two PPDs. Of those with a recorded place of death (N=864), 10.5% died in hospital. 24.8% had an unknown actual or PPD. Of those with a recorded preferred and actual place of death , 83.6% died in PPD. Patients who died at their preferred location had lower overall survival and were more likely to have stayed in a care home. A higher percentage of men compared to females died in a location other than their PPD. CONCLUSIONS Here we present preliminary analysis of patient provided data and their preferences for end-of-life care. We will triangulate these data end-of-life care data from Gliocova project, where we have data on over 50,000 brain tumour patients, to get a more in depth understanding of the patient care in the last months of life.
INVESTIGATING THE ROLE OF LIPID DROPLETS IN MEDULLOBLASTOMA TUMOURS
Authors: Kian Cotton, Maria Victoria Niklison-Chirou
Journal: Neuro-Oncology (2023)

Abstract AIMS Medulloblastomas (MBs) are the most common paediatric brain tumour which originates in the cerebellum. It is classified into four subgroups named: sonic hedgehog, wingless, Group 3 and Group 4. Current treatment for MBs includes surgery, followed by high levels of chemotherapy and radiotherapy. This treatment regime is highly aggressive for the developing brain and produces several significant side effects. Therefore, research into new treatments or improving those already available is crucial to improving patients of life. METHOD It is well-documented that cancer cells have the ability to reprogram their metabolism to support rapid proliferation. These metabolic adaptations will provide the cells with the ability to use alternative sources of energy such as glutamine or lipids. Lipid Droplets (LDs) are highly dynamic cytoplasmic organelles that, under homeostatic conditions, are key in the storage of excess lipids within the cell to provide a buffer against lipotoxicity. Recent research has also begun to describe LDs as more than simple storage molecules but instead as function- ally active organelles. Increases in LD formation have been reported in several cancers such as Glioblastoma RESULTS In this study, we observed that aggressive MB cells have significantly more LDs when compared to non- aggressive MB cells. Further, oleic acid stimulation induced LD formation in MB cells. Finally, in silico gene expression analysis was performed to evaluate the expression of multiple components of the de novo lipid synthesis pathway in medulloblastoma. CONCLUSIONS Our work demonstrates that aggressive MB cells overexpress LDs and therefore identifies them as a possible novel target for MB treatment.
RADIOGENOMIC DATASETS IN GLIOBLASTOMA: AN ESSENTIAL HURDLE
Authors: Prajwal Ghimire, Golestan Karami, Marc Modat, Thomas Booth
Journal: Neuro-Oncology (2023)

Abstract AIMS To evaluate current available datasets for radiogenomic analysis in glioblastoma METHOD A scoping review was performed in the literature from 2000-2023. List of datasets (open access, controlled, paid) available in the literature were tabulated. Qualitative analysis was performed. RESULTS Multiple datasets and data portals were available. Clinical data was available on all portals. MRI and Radiomics datasets were available on The Cancer Imaging Archive(TCIA). Genomics datasets were available in Genomics England (DNA sequencing reads and variants), The Cancer Genome atlas(TCGA) data portal, Chinese cancer genome atlas (CCGA) data portal and The Georgetown Database of Cancer (G-DOC) (sequencing reads, Tran- scriptome profiling, simple nucleotide variation, copy number variation, DNA methylation). Raw datasets were controlled with permission-only access whereas rest were available for access and download on registration. Datasets were available in UK Biobank with a fee. CONCLUSIONS Non-uniformity in datasets is a huge hurdle in pre-processing of the datasets and analysis. Collaborative data portals with user friendly interface are likely to provide uniformity and resolve biases as a part of the hurdle in analysis of these datasets.
REVIEW OF THE INTRODUCTION OF WHOLE GENOME SEQUENCING AS NHS STANDARD OF CARE FOR BRAIN TUMOUR PATIENTS AT QUEEN ELIZABETH HOSPITAL BIRMINGHAM, UK
Authors: Victoria Wykes, Meena Hyatt, Aimee Goel, Shefali Parikh, Fred Berki, Naomi Cole, Sarah Freeth, William Garratt, claire Goddard, Ute Pohl, Santosh Nagaraju, Yasir Chowdhury, Phillip O’Hallaran, Vladimir Petrik, Ismail Ughratdar, Athanasios Zisakis, Helen Benghiat, Sara Meade, Paul Sanghera, Kate Glover, Lowri Hughes, Natasha Vafadar, Yvonne Wallis, Manoj Raghavan, Colin Watts
Journal: Neuro-Oncology (2023)

Abstract AIMS Describe delays in the NHS pathway from initial consent for whole genome sequencing (WGS) to delivery of the final WGS report (WGS-R) to the treating oncologist. Review number of patients with mutations that inform, diagnosis, prognosis or treatment. METHOD Prospective audit of time to key stages along WGS pathway and review of final WGS-R. RESULTS WGS pathway and process: Data snapshot at 24/02/2023 showed 96 patients consented for WGS: 12/96 awaiting surgery; 41/96 awaiting GTAB discussion; 1/96 WGS sample used for histopathological diagnosis, 1/96 ineligible. 41/96 WGS results discussed at a GTAB meeting; 39/44 with complete WGS-R sent to the treating oncologist, including discussion at the local neuro-oncology multi-disciplinary team meeting. Median time from consent to final WGS-R was 225 days (range 145-567). WGS results: 4 patients with glioblastoma (GBM) have RB1 variant, associated with improved progression-free and overall survival (Dono et al 2021). 10 patients had clinically actionable mutations with recommended trials or compassionate-use drugs. 1/10 patient with GBM and High Tumour Mutational Burden who completed standard of care (SOC) treatment has commenced anti-PD1 immunotherapy (Nivolumab; Goodman et al 2017). 5/10 patients are currently on SOC treatment, 3/10 had deteriorated and 1/10 were deceased at time of WGS-R. Excellent concordance of WGS data with SOC genetic/immunohistochemistry testing. No germline mutations identified. CONCLUSIONS Nearly a third of patients had genetic variants that may have the potential to inform future clinical management. Further investment in the WGS pathway is required to deliver timely results to allow application of precision medicine for brain cancer patients.
PROGNOSTIC FACTORS IN NON-SMALL CELL LUNG CANCER METASTATIC TO THE BRAIN
Authors: Daniel Shelley, Pinelopi Gkogkou
Journal: Neuro-Oncology (2023)

Abstract AIMS To identify prognostic factors significantly associated with overall survival in patients with non-small cell lung cancer (NSCLC) metastatic to the brain. To identify whether intracranial or extracranial factors had greater influence on overall survival in this cohort. METHOD Retrospective review of 21 patients from a single UK centre with NSCLC metastatic to the brain was undertaken. Hazard ratios were obtained from the Cox proportional hazards model, and survival curves plotted via the Kaplan-Meier method. RESULTS On univariate analysis, higher Karnofsky Performance Status (KPS) was significantly associated with improved overall survival compared to lower (HR 0.112; 95% CI 0.029 – 0.438) as was stable primary disease relative to progressive primary disease (HR 0.088; 95% CI 0.017 – 0.459). Surgical resection of primary disease was also associated with longer overall survival relative to no resection (HR 0.2713; 95% CI 0.075 – 0.980). Local treatment to brain metastases with either surgery or stereotactic radiosurgery prolonged overall survival relative to no local metastatic treatment (HR 0.1422; 95% CI 0.031 – 0.656). Notable variables not significantly associated with overall survival include number, size and location of metastases as markers of intracranial metastatic burden. CONCLUSIONS Primary disease activity (p = 0.004), KPS (p = 0.002), surgical resection of thoracic disease (p = 0.046) and treatment modality of brain metastasis (p = 0.012) were significant prognostic covariates in this cohort of 21 patients. Extracranial disease and patient factors appear to have greater prognostic significance than intracranial metastatic burden in this patient population.